Carbostyril derivatives represented by the above general formula (1) and a production process thereof are described in Japanese Patent Kokoku (Post-Exam. Publn.) No. 63-35623 (U.S. Pat. No. 4,578,381), and they are known to be useful as anti-ulcerative agents.
In addition, Japanese Patent Kokai (Laid-Open) No. 3-74329 discloses an invention relating to a different use (an agent for treating gastritis) of the same compound as used in the present invention, Japanese Patent Kokai (Laid-Open) No. 3-145468 discloses an invention of a process for producing an optically active substance of the compound used in the present invention, and Japan. J. Pharmacol. Vol. 49, pp. 441-448 (1989) discloses that the compound used in the present invention has activity for inhibiting active oxygen.
According to the classification of diseases of WHO (United Nations-World Health Organization), diabetes mellitus is classified into insulin dependent diabetes mellitus (IDDM) in which acute or sub-acute symptoms are shown owing to the insufficiency of the absolute quantity of insulin and treatment by administration of insulin is necessary; non-insulin dependent diabetes mellitus (NIDDM) in which the progress of diabetes mellitus is slow and treatment by administration of insulin is not always necessary; malnutrition-related diabetes mellitus (MRDM); and chronic hyperglycemia accompanying other maladies and syndromes.
Of these, IDDM is considered to be attributable to the disruption of pancreatic .beta.-cells by autoimmune mechanism. HLA (human leukocyte antigen), cytocaine, virus, etc. are regarded as causes of the disruption of pancreatic .beta.-cells (Koji Nakanishi, Tetsuro Kobayashi and Mitsuru Hara "TONYOBYO GAKU (Diabetes mellitus), 1989" edited by Mikinori Kosaka and Yasuo Akanuma, published by "SHINDAN-TO-CHIRYO SHA", 1989, pp. 226-244).
On the other hand, as the cause of NIDDM, there are considered to exist, for example, insulin-effect disorders caused by various factors such as (1) congenital disorders in pancreas, i.e., disorders of adaptability to an increase of the demand for insulin, and (2) aging, obesity, stress, etc. (Hiroo Imura "TONYOBYO GAKU-NO-SIMPO" (Progress in Treatment of Diabetes Mellitus), 1989, edited by Japan Diabetes Society, published by "SHINDAN-TO-CHIRYO SHA", 1989, pp. 1-12).
However, the onset of diabetes mellitus including IDDM and NIDDM is due to the tangle of hereditary factors and environmental factors, and a considerable part of the onset remains unknown.
PROBLEMS TO BE SOLVED BY THE INVENTION AND MEANS FOR SOLVING THEM
In the course of various studies for developing an anti-diabetes mellitus, the present inventors found that a carbostyril derivative represented by the above general formula (1), in particular, 2-(4-chlorobenzoyl-amino)-3-(2-quinolon-4-yl)propionic acid or a salt thereof, is excellent in activity for lowering blood sugar and activity for protecting pancreas .beta.-cells, has activity for lowering blood sugar and inhibitory effect for increasing insulin value in blood in a pharmacological test using NIDDM-rats OLETF (Otsuka Long Evans Tokushima Fatty) (Kawano, K.; Hirashima, T.; Mori, S.; Kurosumi, M.; Saitoh, Y.; RATS NEWS LETTER, No. 25, pp. 24-26, July, 1991.), and is useful as a preventive and curative drug against insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus, whereby the present invention has been accomplished.
The anti-diabetes mellitus of the present invention is obtained by formulating a carbostyril derivative of the above general formula (1) or a salt thereof into a conventional medicinal preparation form. Such a parathion is prepared using conventional diluents or excipients, such as fillers, bulking agents, binding agents, wetting agents, disintegrating agents, surface active agents, lubricating agents and the like. As the medicinal preparation, various forms can be chosen depending on therapeutical purposes, and typical examples of the preparation form are tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like.
In the case of shaping into the tablet form, as carriers, various carriers heretofore well known to the art can be used, and there can be exemplified excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaoline, crystalline cellulose, silicic acid and the like; binding agents such as water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, shelac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone and the like; disintegrating agents such as dried starch, sodium alginate, agar-agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, esters of polyoxyethylene sorbitan fatty acids, sodium laurylsulfate, stearic acid monoglyceride, starch, lactose and the like; disintegration inhibiting agents such as white sugar, stearin, coconut butter, hydrogenated vegetable oil and the like; absorption promotors such as quaternary ammonium basis, sodium laurylsulfate and the like; wetting agents such as glycerin, starch and the like; adsorbing agents such as starch, lactose, kaoline, bentonite, colloidal silicic acid and the like; lubricants such as purified talc, stearates, boric acid powder, polyethylene glycols and the like. In addition, if necessary, the tablets can be made into coated tablets having a usual coating, for example, tablets coated with sugar, tablets coated with gelatin film, tablets coated with enteric coating layer, tablets coated with films or double layer tablets as well as multiple layer tablets, and the like.
In the case of shaping into the pill form, as carriers, various carriers heretofore well known to the art can be used, and there can be exemplified excipients such as glucose, lactose, starch, coconut butter, hydrogenated vegetable oil, kaoline, talc and the like; binding agents such as gum arabic powder, tragacanth gum powder, gelatin, ethanoland the like; disintegrating agents such as laminalan, agar-agar and the like.
In the case of shaping into the suppository form, as carriers, various heretofore well-known carriers can be used, and there can be exemplified polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthesized glyceride.
In the case of formulation into the injection, the solution and the suspension are sterilized and are preferably isotonic to the blood. For shaping into any of the solution, emulsion and suspension forms, as a diluent, all of those usually used in the art can be used, and there can be exemplified water, ethyl alcohol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, sodium chloride, glucose or glycerin may be incorporated into the curative drug in an amount sufficient to prepare an isotropic solution, and the curative drug may be incorporated with conventional dissolving auxiliaries, buffer solutions, analgesic agents, and optionally coloring materials, preservatives, perfumes, seasoning agents, sweetening agents and other medicines.
Although the amount of the carbostyril derivative (1) or salt thereof to be contained in the anti-diabetes mellitus of the present invention is not critical and is chosen in a wide range, it is usually 1 to 70% by weight, preferably 5 to 50% by weight based on the weight of the whole composition.
A method for administering the anti-diabetes mellitus of the present invention is not critical, and the anti-diabetes mellitus is administered by a method suitable for any of various pharmaceutical forms, the age, sex and other conditions of a patient, the degree of disease, etc. For example, when the anti-diabetes mellitus is any of tablets, pills, a solution, a suspension, an emulsion, granules and capsules, it is orally administered. When the anti-diabetes mellitus is an injection, it is administered intravenously singly or in admixture with usual injectable transfusions of glucose, amino acid, etc., and if necessary, it is administered alone intramuscularly, intracutaneously, subcutaneously or intraperitoneally. When the anti-diabetes mellitus is a suppository, it is administered into rectum.
Although the dose of the anti-diabetes mellitus of the present invention is properly chosen depending on administration route, the age, sex and other conditions of a patient, the degree of disease, etc., the amount of the carbostyril derivative (1) or salt thereof is usually preferably 0.6 to 50 mg per kg of body weight a day. It is preferable to incorporate 10 to 1,000 mg of the active ingredient into an administration unit form.